(S)-CSA Salt Of S-Ketamine, (R)-CSA Salt Of S-Ketamine And Processes For The Preparation Of S-Ketamine

ABSTRACT

The present invention is directed to processes for the preparation of esketamine. The present invention is further directed to processes for the resolution of S-ketamine from a racemic or enantiomerically enriched mixture of ketamine. The present invention is further directed to an (S)-CSA salt of S-ketamine, more particularly a monohydrate form of the (S)-CSA salt of S-ketamine; and to an (R)-CSA salt of R-ketamine.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. patent application Ser. No.15/997,267, filed Jun. 4, 2018, which is a continuation of U.S. patentapplication Ser. No. 15/152,705, filed May 12, 2016, which claims thebenefit of U.S. Provisional Patent Application 62/160,659, filed on May13, 2015, the disclosures of which are incorporated by reference hereinin their entireties.

FIELD OF THE INVENTION

The present invention is directed to processes for the preparation of(S)-ketamine. The present invention is further directed to processes forthe resolution of S-ketamine from a racemic or enantiomerically enrichedmixture of ketamine. The present invention is further directed to an(S)-CSA salt of S-ketamine, more particularly a monohydrate form of the(S)-CSA salt of S-ketamine; and to an (R)-CSA salt of R-ketamine.

BACKGROUND OF THE INVENTION

Ketamine (a racemic mixture of the corresponding S- and R-enantiomers)is an NMDA receptor antagonist, with a wide range of effects in humans,including analgesia, anesthesia, hallucinations, dissociative effects,elevated blood pressure and bronchodilation. Ketamine is primarily usedfor the induction and maintenance of general anesthesia. Other usesinclude sedation in intensive care, analgesia (particularly in emergencymedicine and treatment of bronchospasms. Ketamine has also been shown tobe efficacious in the treatment of depression (particularly in those whohave not responded to current antidepressant treatment). In patientswith major depressive disorders, ketamine has additionally been shown toproduce a rapid antidepressant effect, acting within hours.

The S-ketamine enantiomer (or S-(+)-ketamine or esketamine) has higherpotency or affinity for the NMDA receptor and thus potentially allowingfor lower effective dosages; and is available for medical use,administered either IV (intravenously) or IM (intramuscularly), underthe brand name KETANEST S.

HUDYMA, T. W., et al., in DE 2062620 A published Jul. 15, 1971 describeresolution of ketamine with natural L-tartaric acid. Hudyma et alfurther disclose that attempts at resolution of ketamine withcamphorsulfonic acid (CSA) were unsuccessful. STEINER K., et al., in DE19619665 C2 published Mar. 8, 2001 (US Equiv. U.S. Pat. No. 6,040,479)describe a process for resolution of ketamine using L-tartaric acid inwater or a mixture of water and an alcohol and/or ketone, ether orester. RUSSO, T., et al., in PCT Publication WO2001/098265 (US Equiv.Patent Publication No. 20030212143 A1), published Aug. 15, 2002 describechiral resolution of ketamine using L-tartaric acid in a mixture ofsolvent and water.

There remains a need for a method for the resolution of the S-ketamineenantiomer from racemic ketamine, wherein (a) the process does not usechiral tartaric acid; (b) the process comprises one to three, preferablyone to two crystallization steps (for example, to avoid loss of yield);(c) the process results in a yield of greater than about 25%; (d) theprocess uses solvents which are non-toxic and/or do not require specialhandling; and/or (e) the process is suitable for large scale orcommercial manufacture.

SUMMARY OF THE INVENTION

The present invention is directed to a process for the preparation of amonohydrate form of (S)-camphorsulfonic acid salt of S-ketamine(preferably a crystalline monohydrate form), a compound of formula(I-CSA)

(also known by its IUPAC name of(S)-2-(2-chlorophenyl)-2-(methylammonium)cyclohexanone(+)-camphorsulfonate monohydrate), comprising

reacting ketamine (preferably racemic ketamine) with (S)-camphorsulfonicacid, a known compound, wherein the (S)-camphorsulfonic acid is presentin an amount in the range of from about 0.5 to about 2.0 molarequivalents (relative to the moles of ketamine);

in the presence of water; wherein the water is present in an amount inthe range of from about 3.5% to about 15%;

in an organic solvent; at a temperature in the range of from about 20°C. to about solvent reflux temperature;

to yield the monohydrate form of (S)-CSA salt of S-ketamine;

wherein the monohydrate form of (S)-CSA salt of S-ketamine is present inan enantiomeric excess in the range of from about 50% to about 100%.

The present invention is further directed to a process for thepreparation of S-ketamine hydrochloride (also known as esketamine), acompound of formula (I-HCl)

comprising the steps of

(a) reacting the monohydrate form of (S)-camphorsulfonic acid salt ofS-ketamine (prepared for example as described above) with an inorganicbase; in a solvent or mixture of solvents; preferably in the presence ofwater; to yield S-ketamine as a free base; and

(b) reacting the S-ketamine free base with HCl; to yield thecorresponding S-ketamine hydrochloride salt.

The present invention is directed to a process for the preparation of(R)-camphorsulfonic acid salt of R-ketamine (preferably a crystallineform), a compound of formula (II-CSA)

comprising

reacting ketamine (preferably racemic ketamine) with (R)-camphorsulfonicacid, a known compound, wherein the (R)-camphorsulfonic acid is presentin an amount in the range of from about 0.5 to about 2.0 molarequivalents (relative to the moles of ketamine);

in the presence of water; wherein the water is present in an amount inthe range of from about 3.5% to about 15%;

in an organic solvent; at a temperature in the range of from about 20°C. to about solvent reflux temperature;

to yield a product mixture comprising an (R)-CSA salt of R-ketamine,preferably as a solid, more preferably as a hydrate (for example as amonohydrate), and S-ketamine; wherein the S-ketamine remains insolution;

wherein the (R)-CSA salt of R-ketamine is present in an enantiomericexcess in the range of from about 50% to about 100%.

The present invention is further directed to a process for thepreparation of S-ketamine hydrochloride (also known as esketamine), acompound of formula (I-HCl)

comprising the steps of

Step 1:

reacting ketamine (preferably racemic ketamine) with (R)-camphorsulfonicacid, a known compound, wherein the (R)-camphorsulfonic acid is presentin an amount in the range of from about 0.5 to about 2.0 molarequivalents (relative to the moles of ketamine);

in the presence of water; wherein the water is present in an amount inthe range of from about 3.5% to about 15%; in an organic solvent; at atemperature in the range of from about 20° C. to about solvent refluxtemperature;

to yield a product mixture comprising an (R)-CSA salt of R-ketamine,preferably as a hydrate (for example, as a monohydrate), preferably as asolid, and S-ketamine; wherein the S-ketamine remains in solution; andwherein the (R)-CSA salt of R-ketamine is present in an enantiomericexcess in the range of from about 50% to about 100%

Step 2:

filtering the product mixture (of Step 1) to yield the(R)-camphorsulfonic acid salt of R-ketamine as a solid and a filtratecomprising S-ketamine;

Step 3:

reacting the S-ketamine (in the filtrate or optionally, isolated fromthe filtrate, by, for example, reacting with a suitably selectedinorganic base and extracting with a suitably selected organic solvent)with HCl; to yield the corresponding S-ketamine hydrochloride salt.

The present invention is further directed to a monohydrate form of(S)-CSA salt of S-ketamine, preferably a crystalline monohydrate form of(S)-CSA salt of S-ketamine, as described in detail hereinafter.

The present invention is further directed to an (R)-CSA salt ofR-ketamine, preferably a crystalline form of (R)-CSA salt of R-ketamine,as described in detail hereinafter.

The present invention is further directed to a product preparedaccording to any of the processes described herein.

Illustrative of the invention is a pharmaceutical composition comprisinga pharmaceutically acceptable carrier and a product prepared accordingto any of the process(es) described herein. An illustration of theinvention is a pharmaceutical composition made by mixing a productprepared according to any of the process(es) described herein and apharmaceutically acceptable carrier. Illustrating the invention is aprocess for making a pharmaceutical composition comprising mixing aproduct prepared according to any of the process(es) described hereinand a pharmaceutically acceptable carrier.

Exemplifying the invention are methods of treating a disorder mediatedtreatment resistant depression comprising administering to a subject inneed thereof a therapeutically effective amount of a product preparedaccording to any of the process(es) described herein.

In an embodiment, the present invention is directed to a productprepared according to any of the process(es) described herein for use asa medicament. In another embodiment, the present invention is directedto a product prepared according to any of the process(es) describedherein for use in the treatment of treatment resistant depression. Inanother embodiment, the present invention is directed to a compositioncomprising a product prepared according to any of the process(es)described herein for the treatment of treatment resistant depression.

Another example of the invention is the use of a product preparedaccording to any of the process(es) described herein in the preparationof a medicament for treating treatment resistant depression, in asubject in need thereof. In another example, the present invention isdirected to a product prepared according to any of the process(es)described herein for use in a methods for treating treatment resistantdepression, in a subject in need thereof.

BRIEF DESCRIPTIONS OF THE FIGURE

FIG. 1 illustrates a pXRD spectra for a representative sample of thecrystalline, monohydrate form of the (S)-CSA salt of S-ketamine.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to process(es) for the preparation ofS-ketamine, S-ketamine hydrochloride, S-ketamine•(S)-CSA salt (the(S)-CSA salt of S-ketamine) and a monohydrate (preferably crystalline)form of S-ketamine •(S)-CSA salt. The present invention is directed toprocess(es) for the preparation of R-ketamine •(R)-CSA salt (the (R)-CSAsalt of R-ketamine), preferably a crystalline form of R-ketamine•(R)-CSA salt. The present invention is further directed to process(es)for the resolution of S-ketamine from a racemic (or enantiomericallyenriched mixture) of ketamine.

The present invention is further directed to an (S)-CSA salt ofS-ketamine, preferably, a monohydrate (S)-CSA salt of S-ketamine, morepreferably, a crystalline monohydrate (S)-CSA salt of S-ketamine. Thepresent invention is further directed to an (R)-CSA salt of R-ketamine,preferably, a crystalline (R)-CSA salt of R-ketamine. The presentinvention is further directed to any CSA salt as described herein.

As used herein, unless otherwise noted, the term “ketamine” shall mean aracemic or enantiomerically enriched mixture of ketamine, a compound ofthe following structure

also known as 2-(2-chlorophenyl)-2-(methylamino)cyclohexanone.

As used herein, unless otherwise noted, the term “enantiomericallyenriched mixture” shall mean a mixture of the corresponding (S)- and(R)-enantiomers, wherein one of said enantiomers is present in anenantiomeric excess of greater than about 50%, preferably present in anenantiomeric excess in the range of from about 50% to about 95%, or anyamount or range therein, preferably, in an enantiomeric excess in therange of from about 75% to about 95%.

In an embodiment of the present invention, the ketamine is racemic. Inanother embodiment of the present invention, the ketamine is anenantiomerically enriched mixture, wherein the (S)- or (R)-enantiomer ispresent in an enantiomeric excess of greater than about 50%, preferably,in an enantiomeric excess in the range of from about 50% to about 99%,or any amount or range therein, for example, in an enantiomeric excessof about 51%, 55%, 60%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 90.5%, 91%,91.5%, 92%, 92.5%, 93%, 93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%,97.5%, 98%, 98.5% or 99%.

As used herein, unless otherwise noted, the term “S-ketamine” shall meanthe (S)-enantiomer of ketamine, as a free base, a compound of formula(I)

also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. In anembodiment, S-ketamine is present in an enantiomeric excess of greaterthan about 50%, or any amount or range therein, more preferably in anenantiomeric excess of greater than about 75%, more preferably in anenantiomeric excess of greater than about 85%, more preferably in anenantiomeric excess in the range of from about 90% to about 100%, or anyamount or range therein, more preferably in an enantiomeric excess inthe range of from about 95% to about 99%, for example, in anenantiomeric excess of about 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%,93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.1%,98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%,99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%.

As used herein, unless otherwise noted, the term “esketamine” shall meanthe hydrochloric acid salt of (S)-enantiomer of ketamine, a compound offormula (I-HCl)

also known as (S)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanonehydrochloride.

As used herein, unless otherwise noted, the term “R-ketamine” shall meanthe (R)-enantiomer of ketamine, as a free base, a compound of formula(II)

also known as (R)-2-(2-chlorophenyl)-2-(methylamino)cyclohexanone. In anembodiment, R-ketamine is present in an enantiomeric excess of greaterthan about 50%, or any amount or range therein, more preferably in anenantiomeric excess of greater than about 75%, more preferably in anenantiomeric excess of greater than about 85%, more preferably in anenantiomeric excess in the range of from about 90% to about 100%, or anyamount or range therein, more preferably in an enantiomeric excess inthe range of from about 95% to about 99%, for example, in anenantiomeric excess of about 90%, 90.5%, 91%, 91.5%, 92%, 92.5%, 93%,93.5%, 94%, 94.5%, 95%, 95.5%, 96%, 96.5%, 97%, 97.5%, 98%, 98.1%,98.2%, 98.3%, 98.4%, 98.5%, 98.6%, 98.7%, 98.8%, 98.9%, 99%, 99.1%,99.2%, 99.3%, 99.4%, 99.5%, 99.6%, 99.7%, 99.8%, 99.9% or 100%.

As used herein, unless otherwise noted the term “S-CSA” shall mean(+)-camphorsulfonic acid, also known as (1S,4R)-camphorsulfonic acid. Asused herein, unless otherwise noted, the term “R-CSA” shall mean(−)-camphorsulfonic acid, also known as (1R,4S)-camphorsulfonic acid.(Camphorsulfonic acid is also known by its IUPAC name(7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic acid.)

In an embodiment, the present invention is directed to methods for thetreatment of treatment-refractory or treatment-resistant depression,wherein a product prepared according to any of the process(es) describedherein is administered at a dosage amount in the range of from about0.01 mg to about 1000 mg, or any amount or range therein, preferablyfrom about 0.01 mg to about 500 mg, or any amount or range therein,preferably from about 0.1 mg to about 250 mg, or any amount or rangetherein. In another embodiment, the present invention is directed tomethods for the treatment of treatment-refractory or treatment-resistantdepression, wherein a product prepared according to any of theprocess(es) described herein is administered at a dosage amount in therange of from about 0.01 mg to about 1000 mg, preferably selected fromthe group consisting of 0.01 mg, 0.025 mg, 0.05 mg, 0.1 mg, 0.5 mg, 1mg, 5 mg, 10 mg, 25 mg, 50 mg, 100 mg, 150 mg, 200 mg, 250 mg and 500mg.

As used herein, the notation “*” shall denote the presence of astereogenic center.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Preferably, wherein the compound is present as an enantiomer, theenantiomer is present at an enantiomeric excess of greater than or equalto about 80%, more preferably, at an enantiomeric excess of greater thanor equal to about 90%, more preferably still, at an enantiomeric excessof greater than or equal to about 95%, more preferably still, at anenantiomeric excess of greater than or equal to about 98%, mostpreferably, at an enantiomeric excess of greater than or equal to about99%. Similarly, wherein the compound is present as a diastereomer, thediastereomer is present at an diastereomeric excess of greater than orequal to about 80%, more preferably, at an diastereomeric excess ofgreater than or equal to about 90%, more preferably still, at andiastereomeric excess of greater than or equal to about 95%, morepreferably still, at an diastereomeric excess of greater than or equalto about 98%, most preferably, at an diastereomeric excess of greaterthan or equal to about 99%.

Furthermore, it is intended that within the scope of the presentinvention, any element, in particular when mentioned in relation to acompound of formula (I), shall comprise all isotopes and isotopicmixtures of said element, either naturally occurring or syntheticallyproduced, either with natural abundance or in an isotopically enrichedform. For example, a reference to hydrogen includes within its scope ¹H,²H (D), and ³H (T). Similarly, references to carbon and oxygen includewithin their scope respectively ¹²C, ¹³C and ¹⁴C and ¹⁶O and ¹⁸O. Theisotopes may be radioactive or non-radioactive. Radiolabelled compoundsof formula (I) may comprise a radioactive isotope selected from thegroup of ³H, ¹¹C, ¹⁸F, ¹²²I, ¹²³I, ¹²⁵I, ¹³¹I, ⁷⁵Br, ⁷⁶Br, ⁷⁷Br and⁸²Br. Preferably, the radioactive isotope is selected from the group of³H, ¹¹C and ¹⁸F.

Abbreviations used in the specification, particularly the Schemes andExamples, are as follows:

-   -   CPME=Cyclopentyl methyl ether    -   CSA=Camphorsulfonic acid (IUPAC name        (7,7-dimethyl-2-oxobicyclo[2.2.1]heptan-1-yl)methanesulfonic        acid)    -   DCM=Dichloromethane    -   DMF=N,N-Dimethylformamide    -   DMSO=Dimethyl sulfoxide    -   DSC=Dynamic Scanning calorimetry    -   DVS=Dynamic Vapor Sorption    -   ee or % e.e. =Enantiomeric Excess    -   ¹H NMR=Hydrogen Nuclear Magnetic Resonance    -   MeOH=Methanol    -   MEK=Methyl ethyl ketone    -   2-Me-THF=2-Methyl-tetrahydrofuran    -   ML—Mother Liquor    -   2-PrOH or IPA=2-Propanol (Isopropanol)    -   pXRD=Powder X-Ray Diffraction    -   % RH=% Relative Humidity    -   RT=Room temperature    -   TBME or MTBE=tert-Butyl methyl ether    -   TG-FTIR=ThermoGravimetric-Fourier Transform InfraRed        (Spectroscopy)    -   THF=Tetrahydrofuran    -   v:v=volume:volume ratio

As used herein, unless otherwise noted, the term “isolated form” shallmean that the compound is present in a form which is separate from anysolid mixture with another compound(s), solvent system or biologicalenvironment. In an embodiment of the present invention, a productprepared according to any of the process(es) described herein is presentin an isolated form. In another embodiment, the (S)-CSA salt ofS-ketamine, preferably the monohydrate form of the (S)-CSA salt ofS-ketamine, more preferably the crystalline monohydrate form of the(S)-CSA salt of S-ketamine, is present in an isolated form. In anotherembodiment, the (R)-CSA salt of R-ketamine, preferably the crystallineform of the (R)-CSA salt of R-ketamine, is present in an isolated form.

As used herein, unless otherwise noted, the term “substantially pureform” shall mean that the mole percent of impurities in the isolatedcompound is less than about 5 mole percent, preferably less than about 2mole percent, more preferably, less than about 0.5 mole percent, mostpreferably, less than about 0.1 mole percent. In an embodiment of thepresent invention, a product prepared according to any of theprocess(es) described herein is present as a substantially pure form. Inanother embodiment, the (S)-CSA salt of S-ketamine, preferably themonohydrate form of the (S)-CSA salt of S-ketamine, more preferably thecrystalline monohydrate form of the (S)-CSA salt of S-ketamine, ispresent as a substantially pure form. In another embodiment, the (R)-CSAsalt of R-ketamine, preferably a crystalline form of the (R)-CSA salt ofR-ketamine, is present as a substantially pure form.

As used herein, unless otherwise noted, the term “substantially free ofa corresponding salt form(s)” when used to described the compound offormula (I) shall mean that mole percent of the corresponding saltform(s) in the isolated base of formula (I) is less than about 5 molepercent, preferably less than about 2 mole percent, more preferably,less than about 0.5 mole percent, most preferably less than about 0.1mole percent. In an embodiment of the present invention, a productprepared according to any of the process(es) described herein is presentin a form which is substantially free of corresponding salt form(s). Inanother embodiment, the (S)-CSA salt of S-ketamine, preferably themonohydrate form of the (S)-CSA salt of S-ketamine, more preferably thecrystalline monohydrate form of (S)-CSA salt of S-ketamine, is presentin a form which is substantially free of corresponding salt form(s). Inanother embodiment, the (R)-CSA salt of R-ketamine, preferably acrystalline form of the (R)-CSA salt of R-ketamine, is present in a formwhich is substantially free of corresponding salt form(s).

As used herein, the term “treatment-refractory or treatment-resistantdepression” and the abbreviation “TRD” shall be defined as majordepressive disorder that does not respond to adequate courses of atleast two antidepressants, preferably two or more antidepressants, morepreferably two to three, antidepressants.

One skilled in the art will recognize that the failure to respond to anadequate course of a given antidepressant may be determinedretrospectively or prospectively. In an embodiment, at least one of thefailures to respond to an adequate course of antidepressant isdetermined prospectively. In another embodiment, at least two of thefailures to respond to an adequate course of antidepressant aredetermined prospectively. In another embodiment, at least one of thefailures to respond to an adequate course of antidepressant isdetermined retrospectively. In another embodiment, at least two of thefailures to respond to an adequate course of antidepressant aredetermined retrospectively.

As used herein, unless otherwise noted, the terms “treating”,“treatment” and the like, shall include the management and care of asubject or patient (preferably mammal, more preferably human) for thepurpose of combating a disease, condition, or disorder and includes theadministration of a compound of the present invention to prevent theonset of the symptoms or complications, alleviate the symptoms orcomplications, or eliminate the disease, condition, or disorder.

As used herein, unless otherwise noted, the term “prevention” shallinclude (a) reduction in the frequency of one or more symptoms; (b)reduction in the severity of one or more symptoms; (c) the delay oravoidance of the development of additional symptoms; and/or (d) delay oravoidance of the development of the disorder or condition.

One skilled in the art will recognize that wherein the present inventionis directed to methods of prevention, a subject in need of thereof (i.e.a subject in need of prevention) shall include any subject or patient(preferably a mammal, more preferably a human) who has experienced orexhibited at least one symptom of the disorder, disease or condition tobe prevented. Further, a subject in need thereof may additionally be asubject (preferably a mammal, more preferably a human) who has notexhibited any symptoms of the disorder, disease or condition to beprevented, but who has been deemed by a physician, clinician or othermedical profession to be at risk of developing said disorder, disease orcondition. For example, the subject may be deemed at risk of developinga disorder, disease or condition (and therefore in need of prevention orpreventive treatment) as a consequence of the subject's medical history,including, but not limited to, family history, pre-disposition,co-existing (comorbid) disorders or conditions, genetic testing, and thelike.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment. Preferably, the subject has experiencedand/or exhibited at least one symptom of the disease or disorder to betreated and/or prevented.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

Optimal dosages to be administered may be readily determined by thoseskilled in the art, and will vary with the particular compound orcompounds used, the mode of administration, the strength of thepreparation and the advancement of the disease condition. In addition,factors associated with the particular patient being treated, includingpatient's sex, age, weight, diet, time of administration and concomitantdiseases, will result in the need to adjust dosages.

One skilled in the art will recognize that, both in vivo and in vitrotrials using suitable, known and generally accepted cell and/or animalmodels are predictive of the ability of a test compound to treat orprevent a given disorder.

One skilled in the art will further recognize that human clinical trialsincluding first-in-human, dose ranging and efficacy trials, in healthypatients and/or those suffering from a given disorder, may be completedaccording to methods well known in the clinical and medical arts.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

To provide a more concise description, some of the quantitativeexpressions given herein are not qualified with the term “about”. It isunderstood that whether the term “about” is used explicitly or not,every quantity given herein is meant to refer to the actual given value,and it is also meant to refer to the approximation to such given valuethat would reasonably be inferred based on the ordinary skill in theart, including approximations due to the experimental and/or measurementconditions for such given value.

To provide a more concise description, some of the quantitativeexpressions herein are recited as a range from about amount X to aboutamount Y. It is understood that wherein a range is recited, the range isnot limited to the recited upper and lower bounds, but rather includesthe full range from about amount X through about amount Y, or any amountor range therein.

Wherein the enantiomeric excess expressions recited herein state thatthe % ee is greater than about X %, said expression is understood tomean a range from an enantiomeric excess of greater than about X % toabout 100%, or any amount or range therein.

Examples of suitable solvents, bases, reaction temperatures, and otherreaction parameters and components are provided in the detaileddescription which follows herein. One skilled in the art will recognizethat the listing of said examples is not intended, and should not beconstrued, as limiting in any way the invention set forth in the claimswhich follow thereafter.

As more extensively provided in this written description, terms such as“reacting” and “reacted” are used herein in reference to a chemicalentity that is any one of: (a) the actually recited form of suchchemical entity, and (b) any of the forms of such chemical entity in themedium in which the compound is being considered when named.

One skilled in the art will recognize that, where not otherwisespecified, the reaction step(s) is performed under suitable conditions,according to known methods, to provide the desired product. One skilledin the art will further recognize that, in the specification and claimsas presented herein, wherein a reagent or reagent class/type (e.g. base,solvent, etc.) is recited in more than one step of a process, theindividual reagents are independently selected for each reaction stepand may be the same of different from each other. For example whereintwo steps of a process recite an organic or inorganic base as a reagent,the organic or inorganic base selected for the first step may be thesame or different than the organic or inorganic base of the second step.Further, one skilled in the art will recognize that wherein a reactionstep of the present invention may be carried out in a variety ofsolvents or solvent systems, said reaction step may also be carried outin a mixture of the suitable solvents or solvent systems. One skilled inthe art will further recognize that wherein two consecutive reaction orprocess steps are run without isolation of the intermediate product(i.e. the product of the first of the two consecutive reaction orprocess steps), then the first and second reaction or process steps maybe run in the same solvent or solvent system; or alternatively may berun in different solvents or solvent systems following solvent exchange,which may be completed according to known methods.

One skilled in the art will further recognize that the reaction orprocess step(s) as herein described (or claimed) are allowed to proceedfor a sufficient period of time until the reaction is complete, asdetermined by any method known to one skilled in the art, for example,chromatography (e.g. HPLC). In this context a “completed reaction orprocess step” shall mean that the reaction mixture contains asignificantly diminished amount of the starting material(s)/reagent(s)and a significantly reduced amount of the desired product(s), ascompared to the amounts of each present at the beginning of thereaction.

Chiral HPLC against a standard may be used to determine percentenantiomeric excess (% ee). The enantiomeric excess may be calculated asfollows

[(Rmoles−Smoles)/(Rmoles+Smoles)]×100%

where Rmoles and Smoles are the R and S mole fractions in the mixturesuch that Rmoles+Smoles=1. The enantiomeric excess may alternatively becalculated from the specific rotations of the desired enantiomer and theprepared mixture as follows:

ee=([α-obs]/[α-max])×100.

For use in medicine, the salts of the compounds of this invention referto non-toxic “pharmaceutically acceptable salts.” Other salts may,however, be useful in the preparation of compounds according to thisinvention or of their pharmaceutically acceptable salts. Suitablepharmaceutically acceptable salts of the compounds include acid additionsalts which may, for example, be formed by mixing a solution of thecompound with a solution of a pharmaceutically acceptable acid such ashydrochloric acid, sulfuric acid, fumaric acid, maleic acid, succinicacid, acetic acid, benzoic acid, citric acid, tartaric acid, carbonicacid or phosphoric acid. Furthermore, where the compounds of theinvention carry an acidic moiety, suitable pharmaceutically acceptablesalts thereof may include alkali metal salts, e.g., sodium or potassiumsalts; alkaline earth metal salts, e.g., calcium or magnesium salts; andsalts formed with suitable organic ligands, e.g., quaternary ammoniumsalts. Thus, representative pharmaceutically acceptable salts include,but are not limited to, the following: acetate, benzenesulfonate,benzoate, bicarbonate, bisulfate, bitartrate, borate, bromide, calciumedetate, camsylate, carbonate, chloride, clavulanate, citrate,dihydrochloride, edetate, edisylate, estolate, esylate, fumarate,gluceptate, gluconate, glutamate, glycollylarsanilate, hexylresorcinate,hydrabamine, hydrobromide, hydrochloride, hydroxynaphthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, N-methylglucamine ammonium salt, oleate, pamoate(embonate), palmitate, pantothenate, phosphate/diphosphate,polygalacturonate, salicylate, stearate, sulfate, subacetate, succinate,tannate, tartrate, teoclate, tosylate, triethiodide and valerate.

Representative acids which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: acids including acetic acid, 2,2-dichloroacetic acid,acylated amino acids, adipic acid, alginic acid, ascorbic acid,L-aspartic acid, benzenesulfonic acid, benzoic acid, 4-acetamidobenzoicacid, (+)-camphoric acid, cam phorsulfonic acid,(+)-(1S)-camphor-10-sulfonic acid, capric acid, caproic acid, caprylicacid, cinnamic acid, citric acid, cyclamic acid, dodecylsulfuric acid,ethane-1,2-disulfonic acid, ethanesulfonic acid,2-hydroxy-ethanesulfonic acid, formic acid, fumaric acid, galactaricacid, gentisic acid, glucoheptonic acid, D-gluconic acid, D-glucuronicacid, L-glutamic acid, α-oxo-glutaric acid, glycolic acid, hippuricacid, hydrobromic acid, hydrochloric acid, (+)-L-lactic acid,(±)-DL-lactic acid, lactobionic acid, maleic acid, (−)-L-malic acid,malonic acid, (±)-DL-mandelic acid, methanesulfonic acid,naphthalene-2-sulfonic acid, naphthalene-1,5-disulfonic acid,1-hydroxy-2-naphthoic acid, nicotinic acid, nitric acid, oleic acid,orotic acid, oxalic acid, palmitic acid, pamoic acid, phosphoric acid,L-pyroglutamic acid, salicylic acid, 4-amino-salicylic acid, sebacicacid, stearic acid, succinic acid, sulfuric acid, tannic acid,(+)-L-tartaric acid, thiocyanic acid, p-toluenesulfonic acid andundecylenic acid.

Representative bases which may be used in the preparation ofpharmaceutically acceptable salts include, but are not limited to, thefollowing: bases including ammonia, L-arginine, benethamine, benzathine,calcium hydroxide, choline, deanol, diethanolamine, diethylamine,2-(diethylamino)-ethanol, ethanolamine, ethylenediamine,N-methyl-glucamine, hydrabamine, 1H-imidazole, L-lysine, magnesiumhydroxide, 4-(2-hydroxyethyl)-morpholine, piperazine, potassiumhydroxide, 1-(2-hydroxyethyl)-pyrrolidine, secondary amine, sodiumhydroxide, triethanolamine, tromethamine and zinc hydroxide.

Resolution of Ketamine (General Methods)

The present invention is directed to a process for the resolution ofketamine into its enantiomers, and more particularly, to processes forthe preparation of an (S)-CSA salt of S-ketamine and an HCl salt ofS-ketamine, as described in more detail in Scheme 1, below.

Accordingly, ketamine (preferably racemic ketamine) is reacted with(S)-camphorsulfonic acid (also known as (+)-CSA or S-CSA)), a knowncompound; wherein the (S)-CSA is present in an amount in the range offrom about 0.5 to about 2.0 molar equivalents (relative to the amount ofketamine), or any amount or range therein, preferably in an amount inthe range of from about 0.75 to about 1.2 molar equivalents, morepreferably, in an amount in the range of from about 0.9 to about 1.1molar equivalents, more preferably, in an amount of about 1 molarequivalent;

in the presence of water; wherein the water is present in an amount inthe range of from about 3.5% to about 15% (by weight in the solvent), orany amount or range therein, preferably in an amount in the range offrom about 3.8% to about 11%, more preferably in an amount in the rangeof from about 5% to about 10%, more preferably in an amount in the rangeof from about 6% and about 8% (for example about 6.7%);

in a suitably selected organic solvent such as a suitably selected ether(for example a cyclic ether) such as THF, 2-methyl-THF, and the like, ora suitably selected ketone such as methyl ethyl ketone, acetone, methylisobutyl ketone, and the like, preferably methyl ethyl ketone or2-methyl-THF, more preferably 2-methyl-THF; at a temperature in therange of from about 20° C. to about solvent reflux temperature, or anytemperature or range therein, preferably at a temperature in the rangeof from about 30° C. to about 100° C., more preferably at a temperaturein the range of from about 50° C. to about 80° C. (for example at about70° C., at about 75° C., at about 80° C., at about 100° C.);

to yield the corresponding monohydrate (S)-CSA salt of S-ketamine,preferably as a solid, more preferably as a crystalline solid; whereinthe monohydrate (S)-CSA salt of S-ketamine is preferably present in anenantiomeric excess of greater than about 50%, preferably in anenantiomeric excess in the range of from about 50% to about 100%, or anyamount or range therein, more preferably, in an enantiomeric excess inthe range of from about 75% to about 100%, more preferably, morepreferably, in an enantiomeric excess in the range of from about 80% toabout 100%, more preferably, in an enantiomeric excess in the range offrom about 90% to about 100%, more preferably, in an enantiomeric excessin the range of from about 98% to about 100%. In an example, themonohydrate (S)-CSA salt of S-ketamine is prepared in an enantiomericexcess of greater than or equal to about 90%. In another example, themonohydrate (S)-CSA salt of S-ketamine is prepared in an enantiomericexcess of greater than or equal to about 96%.

Preferably, the monohydrate (S)-CSA salt of S-ketamine is isolated byknown methods, for example by filtration.

One skilled in the art will recognize that the product mixture resultingfrom the above reaction of ketamine with (S)-CSA will comprise themonohydrate (S)-CSA salt of S-ketamine (as a precipitate or suspension)and R-ketamine (protonated, in solution). Further, one skilled in theart will recognize, that following filtration of the monohydrate (S)-CSAsalt of S-ketamine, the mother liquor or filtrate will compriseenantiomerically enriched R-ketamine.

The monohydrate (S)-CSA salt of S-ketamine is optionally recrystallized,according to known methods, from a suitably selected solvent or mixtureof solvents, (for example from THF, methyl ethyl ketone or a mixture ofTHF and water), preferably in the presence of (or in a mixture with)water.

The monohydrate (S)-CSA salt of S-ketamine is further optionally reactedwith a suitably selected base, preferably an inorganic base such asK₂CO₃, Na₂CO₃, NaHCO₃, NaOH, KOH, and the like, preferably K₂CO₃;wherein the base is preferably present in an amount in the range of fromabout 1.0 to about 10 molar equivalents (relative to the moles of themonohydrate (S)-CSA salt of S-ketamine), preferably in the range of fromabout 1.0 to about 5.0 molar equivalents, more preferably in a range offrom about 1.0 to about 2.0 molar equivalents (for example, about 1.2molar equivalents);

in a suitably selected solvent such as isopropyl acetate, ethyl acetate,toluene, and the like, preferably isopropyl acetate; preferably asolvent which is not miscible with water; to yield the correspondingS-ketamine, as a free base. One skilled in the art will recognize thatthe enantiomeric excess of the S-ketamine base will be approximatelyequal to the enantiomeric excess of the monohydrate (S)-CSA salt ofS-ketamine, since the reaction with the inorganic base would not beexpected to affect the stereo-center (e.g. result in racemization at thestereo-center).

Preferably, the S-ketamine free base is isolated according to knownmethods, for example by filtration.

The S-ketamine free base is further optionally reacted, according toknown methods, with a suitably selected acid such as HCl (for example asHCl gas), to yield the corresponding acid addition salt, preferably thecorresponding hydrochloride salt. One skilled in the art will recognizethat the enantiomeric excess of the S-ketamine salt, preferably theS-ketamine hydrochloride salt will be approximately equal to or greaterthan the enantiomeric excess of the S-ketamine, since the reaction withthe suitably selected acid would not be expected to affect thestereo-center (e.g. result in racemization at the stereo-center).

In an embodiment of the present invention, the S-ketamine free base isreacted with the acid, preferably HCl, wherein the amount of the acid isin the range of from about 0.8 to about 5.0 molar equivalents (relativeto the moles of S-ketamine base), more preferably in an amount in therange of rom about 1.0 to about 3.0 molar equivalents, more preferablyin an amount in the range of from about 1.0 to about 1.5 molarequivalents (for example about 1.2 molar equivalents).

The present invention is further directed to a process for theresolution of ketamine into its enantiomers, and more particularly, to aprocess for the preparation of an (R)-CSA salt of R-ketamine and an HClsalt of S-ketamine, as described in more detail in Scheme 2, below.

Accordingly, ketamine (preferably racemic ketamine) is reacted with(R)-camphorsulfonic acid (also known as (−)-CSA or R-CSA)), a knowncompound; wherein the (R)-CSA is present in an amount in the range offrom about 0.5 to about 2.0 molar equivalents (relative to the amount ofketamine), or any amount or range therein, preferably in an amount inthe range of from about 0.75 to about 1.5 molar equivalents, for examplein an amount of about 1.0 molar equivalents;

in the presence of water; wherein the water is present in an amount inthe range of from about 3.5% to about 15% (by weight in the solvent), orany amount or range therein, preferably in an amount in the range offrom about 7.5% to about 12.5%, for example in an amount of about 9%;

in a suitably selected organic solvent such as a suitably selected ether(for example a cyclic ether) such as THF, 2-methyl-THF, and the like, ora suitably selected ketone such as methyl ethyl ketone, acetone, methylisobutyl ketone, and the like, preferably methyl ethyl ketone or2-methyl-THF, more preferably 2-methyl-THF; at a temperature in therange of from about 20° C. to about solvent reflux temperature, or anytemperature or range therein, preferably at a temperature in the rangeof from about 30° C. to about 100° C.;

to yield a product mixture comprising

(a) the corresponding (R)-CSA salt of R-ketamine, preferably, as ahydrate (for example, as a monohydrate), preferably as a solid, morepreferably as a crystalline solid (for example, as a precipitate);wherein the (R)-CSA salt of R-ketamine is preferably present in anenantiomeric excess of greater than about 50%, preferably in anenantiomeric excess in the range of from about 50% to about 100%, or anyamount or range therein, more preferably, in an enantiomeric excess inthe range of from about 75% to about 100%, more preferably, in anenantiomeric excess of about 96%, more preferably, in an enantiomericexcess in the range of from about 98% to about 100%; and

(b) S-ketamine; wherein the S-ketamine remains in solution; wherein theS-ketamine is preferably present in an enantiomeric excess of greaterthan about 50%, preferably in an enantiomeric excess in the range offrom about 50% to about 100%, or any amount or range therein, morepreferably, in an enantiomeric excess in the range of from about 75% toabout 100%, more preferably, in an enantiomeric excess of about 96%,more preferably, in an enantiomeric excess in the range of from about98% to about 100%.

Although not intended to be limiting or definitive, it is theorized thatthe S-ketamine, which remains in solution in the product mixturedescribed above, may present in a protonated base form (protonated byany excess (R)-CSA present).

Preferably, the (R)-CSA salt of R-ketamine is isolated according toknown methods, for example by filtration. One skilled in the art willrecognize that filtration of the product mixture will yield the (R)-CSAsalt of R-ketamine as a solid and a filtrate or mother liquor comprisingS-ketamine.

The S-ketamine is then further optionally isolated from the filtrate ormother liquor (according to known methods, for example by reacting witha suitably selected inorganic base such as K₂CO₃, Na₂CO₃, NaHCO₃, NaOH,KOH, and the like, and further extracting with a suitably selectedorganic solvent, preferably an organic solvent which is not misciblewith water, such as 2-methyl-THF, isopropyl acetate, and the like,preferably isopropyl acetate) and/or reacted (according to knownmethods), with a suitably selected acid such as HCl (for example as HClgas), to yield the corresponding acid addition salt, preferably thecorresponding hydrochloride salt. One skilled in the art will recognizethat the enantiomeric excess of the S-ketamine salt, preferably theS-ketamine hydrochloride salt will be approximately equal to or greaterthan the enantiomeric excess of the S-ketamine, since the reaction withthe suitably selected acid would not be expected to affect thestereo-center (e.g. result in racemization at the stereo-center).

In an embodiment of the present invention, the S-ketamine is reactedwith the acid, preferably HCl, wherein the amount of the acid is in therange of from about 0.8 to about 5.0 molar equivalents (relative to themoles of S-ketamine base), more preferably in an amount in the range ofrom about 1.0 to about 3.0 molar equivalents, more preferably in anamount in the range of from about 1.0 to about 1.5 molar equivalents(for example about 1.2 molar equivalents).

Crystalline Forms

The crystalline forms of the present invention, for example themonohydrate form of the (S)-CSA salt of S-ketamine may be characterizedby, for example, powder X-Ray Diffraction (pXRD), TG-FTIR, DSC, DVS,Karl-Fischer analysis, optical rotation, and other known methods fordetermining the physical properties of a solid or crystal.

The powder X-ray diffractograms (diffraction spectra, pXRD) providedherein were measured using on an X-ray diffractometer using CuKαradiation. The pestled sample was back-loaded into a conventional x-rayholder. The sample was scanned from 3 to 40° 20 with a step size of0.01° 20 and a time per step of 5.0 seconds. Instrument voltage andcurrent settings were 40 kV and 30 mA.

ThermoGravimetric-Fourier Transform InfraRed (TG-FTIR) measurements,where carried out were measures using a Netzsche Thermo-MicrobalanceTG209 with Bruker FT-IR Spectrometer Vector 22, with aluminum cruciblewith microhoel, nitrogen atmosphere and scanning form 25° C. to 300° C.at a heating rate of 10K/min.

Dynamic Scanning calorimetry (DSC) measurements (where completed) weremeasured using either (a) Perkins Elmer DSC 7, hermetically closed goldcrucible, measuring from 20° C. to 270° C. at a heating rate of 10K/min,(b) TA Instruments DSC Q2000, hermetically closed gold crucible,measuring from 20° C. to 300° C. at a heating rate of 10K/min.

Dynamic Vapor Sorption (DVS) measurements (where completed) weremeasured using a Projekt Messtechnik Sorptions Prufsystem SPS 11 orSurface Measurement Systems DVS-1 scanning (cycling relative humidityand holding the sample at a set relative humidity) as follow: (a)holding sample at 50% RH for 2 hours; (b) 50% RH to 0% RH (5%/h);holding at 0% RH for 5 hours; (c) 0% RH to 95% RH (5%/h); holding at 95%RH for 5 hours; and (d) 95% RH to 50% RH (5%/h); holding at 50% RH for 2hours.

A powder XRD (pXRD) diffractogram was measured for multiple samples ofthe crystalline monohydrate form of (S)-CSA salt of S-ketamine (preparedas described herein), with a representative example as shown in FIG. 1.The crystalline monohydrate form of (S)-CSA salt of S-ketamine, may becharacterized by its X-ray diffraction pattern, comprising peaks havinga relative intensity greater than or equal to about 5%, as listed inTable 1, below.

TABLE 1 pXRD Peaks for Monohydrate (S)-CSA salt of S-Ketamine position[°2θ] d-spacing [Å] relative intensity [%] 7.76 11.38 58.03 8.11 10.8921.58 12.75 6.94 24.89 13.13 6.74 55.99 13.31 6.65 23.96 13.64 6.4931.52 14.92 5.93 100.00 15.51 5.71 32.12 15.71 5.64 28.46 17.09 5.186.03 17.26 5.13 8.92 18.20 4.87 7.73 18.45 4.80 43.84 19.43 4.56 7.3920.10 4.41 10.03 21.29 4.17 12.49 22.38 3.97 14.87 22.58 3.93 6.88 22.713.91 7.31 23.26 3.82 10.45 23.66 3.76 7.90 24.22 3.67 25.66 25.26 3.5228.46 25.68 3.47 5.35 25.93 3.43 8.92 26.76 3.33 13.93 27.33 3.26 51.3228.21 3.16 12.32 29.13 3.06 11.05 29.85 2.99 7.90 31.31 2.86 7.48 32.122.78 8.24 32.79 2.73 7.90 33.10 2.70 6.20 33.72 2.66 7.48 34.95 2.567.48 36.20 2.48 9.77 37.17 2.42 6.03

In an embodiment, the crystalline monohydrate form of (S)-CSA salt ofS-ketamine is characterized by its pXRD pattern which comprises peakshaving a relative intensity greater than or equal to about 10%, aslisted in Table 2, below.

TABLE 2 pXRD Peaks for Monohydrate (S)-CSA salt of S-Ketamine position[°2θ] d-spacing [Å] relative intensity [%] 7.76 11.38 58.03 8.11 10.8921.58 12.75 6.94 24.89 13.13 6.74 55.99 13.31 6.65 23.96 13.64 6.4931.52 14.92 5.93 100.00 15.51 5.71 32.12 15.71 5.64 28.46 18.45 4.8043.84 21.29 4.17 12.49 22.38 3.97 14.87 23.26 3.82 10.45 24.22 3.6725.66 25.26 3.52 28.46 26.76 3.33 13.93 27.33 3.26 51.32 28.21 3.1612.32 29.13 3.06 11.05

In another embodiment, the crystalline monohydrate form of (S)-CSA saltof S-ketamine is characterized by its pXRD pattern which comprises peakshaving a relative intensity greater than or equal to about 20%, aslisted in Table 3, below.

TABLE 3 pXRD Peaks for Monohydrate (S)-CSA salt of S-Ketamine position[°2θ] d-spacing [Å] relative intensity [%] 7.76 11.38 58.03 8.11 10.8921.58 12.75 6.94 24.89 13.13 6.74 55.99 13.31 6.65 23.96 13.64 6.4931.52 14.92 5.93 100.00 15.51 5.71 32.12 15.71 5.64 28.46 18.45 4.8043.84 24.22 3.67 25.66 25.26 3.52 28.46 27.33 3.26 51.32

Water content was measured under adequate exclusion of atmosphericmoisture using a modified volumetric Karl-Fischer titration for ketones,as follows. About 500 mg of the sample was weighed accurately and wasdissolved in 40 mL of the Hydranal®-KetoSolver from Fluka (pre-titratedwith the Karl-Fischer reagent Hydranal®-Composite 5K, from Fluka).Afterwards, the solution was titrated with the Karl-Fischer reagent. Theendpoint was detected voltammetrically and the water content in percentwas calculated according to the following formula:

Water content [%]=V*F*0.1/S

where S represents Sample weight [g], F represents Factor ofKarl-Fischer reagent [mg/mL], and V represents Consumption ofKarl-Fischer reagent [mL].

The % water content was determined for multiple samples of crystallinemonohydrate form of (S)-CSA salt of S-ketamine (prepared as describedherein) with measured values ranging between 3.76% and 3.79% (averagewater content was 3.8%). The calculated theoretical value for amonohydrate of (S)-CSA salt of S-ketamine is 3.7%.

TG-FTIR measurement of a representative sample of the monohydratecrystalline form of (S)-CSA salt of S-ketamine exhibited a weight lossof 3.7 wt % in one step between 110° C. and 190° C. due to evaporationof water (corresponding to the theoretical 3.69 wt % stoichiometricwater content of a monohydrate) and a chemical decomposition above 230°C.

The absolute optical rotation of multiple samples of monohydrate form of(S)-CSA salt of S-ketamine (prepared as described herein) was determinedto range between 66.8° and 67.4°. Average absolute optical rotation was[α]²⁰ _(D)=+67.8° (c=1.0, methanol).

Optical microscopy on the crystalline form of the monohydrate (S)-CSAsalt of S-ketamine showed 1000-50 μM large equant crystals, appearing asfractured blocks. ¹H NMR of a representative sample of the monohydrate(S)-CSA salt of S-ketamine confirmed the 1:1 salt stoichiometry.

DSC measured for a representative sample of the monohydrate (S)-CSA saltof S-ketamine exhibited a melting point of about 144° C., and a meltingenthalpy of 121 J/g. DVS measurement of a representative sample of themonohydrate (S)-CSA salt of S-ketamine exhibited no hygroscopicity, andphysical stability at elevated relative humidity.

The approximate solubility of the monohydrate crystalline form of the(S)-CSA salt of S-ketamine was measured by stepwise dilution of asuspension of about 10 mg of the sample in 0.05 mL solvent. Table 4below lists the approximate solubility, denoted “S”. If a sample was notdissolved by addition of a total of 10-12 mL of solvent, the solubilityis indicated as <1 mg/mL in the Table 4, below.

TABLE 4 Approximate Solubility of Crystalline, Monohydrate Form of(S)-CSA salt of S-Ketamine Solvent or Mixture Solubility (mg/mL) acetone5 < S < 6 anisole    S < 1 DCM  67 < S < 101 1,4-dioxane 5 < S < 6 DMF 91 < S < 185 DMSO 106 < S < 212 ethyl acetate    S < 1 ethanol  67 < S< 100 heptane    S < 1 acetonitrile 22 < S < 24 methanol 226 < S    2-methyl-THF 5 < S < 7 2-propanol 22 < S < 25 isopropyl acetate    S < 1TBME    S < 1 THF 5 < S < 7 toluene    S < 1 water 20 < S < 24 1:1acetone:water 58 < S < 77 10:1 acetone:water 20 < S < 24 2-methyl THFsaturated with water 6 < S < 8 1:1 2-propanol:water  93 < S < 189 10:12-propanol:water 24 < S < 28 1:1 2-propanol:isopropyl acetate 10 < S <11

Additionally, the solubility of the monohydrate crystalline form of the(S)-CSA salt of S-ketamine in select solvents was determined as follows:21 g of (S)-CSA salt of S-ketamine was dissolved in 100 mL of solvent(as listed in Table 5 below). After 24 hours, the solutions wereanalyzed visually. If the compound was completely dissolved, solubilitywas above 20 g/100 mL. If the compound was not completely dissolved, anyremaining precipitate was filtered off, the filtrate was diluted400-fold with HPLC dilution solvent (or acetonitrile/HPLC dilutionsolvent) and analyzed by HPLC, with results as listed in Table 5, below.

TABLE 5 Solubility Measurements(S)-Ketamine-(+)-10-camphorsulfonate-monohydrate Solubility [g/100 mL]Solvent at 23.6° C. demineralized water 5.344 methanol 18.457 ethanol18.297 2-propanol 7.275 acetone (2-propanone) 0.578N,N-dimethylacetamide 18.200 N,N-dimethylformamide 18.267 acetic acid18.209 dichloromethane/methanol 18.589 (50/50 v/v)

The present invention is further directed to an amorphous form of the(S)-CSA salt of S-ketamine. In an embodiment of the present invention,the amorphous form of the (S)-CSA salt of S-ketamine is anhydrous.

The amorphous, anhydrous form of the (S)-CSA salt of S-ketamine may beprepared by dehydrating the monohydrate form at an elevated temperature,for example at a temperature greater than about 120° C. In an example, asample of the monohydrate crystalline form of (S)-CSA salt of S-ketaminewas maintained at 160° C. under dry nitrogen flow for 30 min. pXRDanalysis carried out several hours later showed a mixture of thecrystalline monohydrate and amorphous anhydrous forms of (S)-CSA salt ofS-ketamine. The amorphous anhydrous form of (S)-CSA salt of S-ketaminewas also obtained (in a mixture with the monohydrate form) by slurryingthe crystalline monohydrate form of (S)-CSA salt of S-ketamine in2-methyl THF or isopropyl acetate at about 80° C. for about 4 days.

The amorphous, anhydrous form of (S)-CSA salt of S-ketamine ishygroscopic and rapidly converts to the monohydrate form of (S)-CSA saltof S-ketamine on storage at ambient conditions.

The present invention further comprises pharmaceutical compositionscontaining a product prepared according to any of the process(es)described herein with a pharmaceutically acceptable carrier.Pharmaceutical compositions containing one or more of the compounds ofthe invention described herein as the active ingredient can be preparedby intimately mixing the compound or compounds with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques.The carrier may take a wide variety of forms depending upon the desiredroute of administration (e.g., oral, parenteral). Thus for liquid oralpreparations such as suspensions, elixirs and solutions, suitablecarriers and additives include water, glycols, oils, alcohols, flavoringagents, preservatives, stabilizers, coloring agents and the like; forsolid oral preparations, such as powders, capsules and tablets, suitablecarriers and additives include starches, sugars, diluents, granulatingagents, lubricants, binders, disintegrating agents and the like. Solidoral preparations may also be coated with substances such as sugars orbe enteric-coated so as to modulate major site of absorption. Forparenteral administration, the carrier will usually consist of sterilewater and other ingredients may be added to increase solubility orpreservation. Injectable suspensions or solutions may also be preparedutilizing aqueous carriers along with appropriate additives.

To prepare the pharmaceutical compositions of this invention, one ormore compounds of the present invention as the active ingredient isintimately admixed with a pharmaceutical carrier according toconventional pharmaceutical compounding techniques, which carrier maytake a wide variety of forms depending of the form of preparationdesired for administration, e.g., oral or parenteral such asintramuscular. In preparing the compositions in oral dosage form, any ofthe usual pharmaceutical media may be employed. Thus, for liquid oralpreparations, such as for example, suspensions, elixirs and solutions,suitable carriers and additives include water, glycols, oils, alcohols,flavoring agents, preservatives, coloring agents and the like; for solidoral preparations such as, for example, powders, capsules, caplets,gelcaps and tablets, suitable carriers and additives include starches,sugars, diluents, granulating agents, lubricants, binders,disintegrating agents and the like. Because of their ease inadministration, tablets and capsules represent the most advantageousoral dosage unit form, in which case solid pharmaceutical carriers areobviously employed. If desired, tablets may be sugar coated or entericcoated by standard techniques. For parenterals, the carrier will usuallycomprise sterile water, through other ingredients, for example, forpurposes such as aiding solubility or for preservation, may be included.Injectable suspensions may also be prepared, in which case appropriateliquid carriers, suspending agents and the like may be employed. Thepharmaceutical compositions herein will contain, per dosage unit, e.g.,tablet, capsule, powder, injection, teaspoonful and the like, an amountof the active ingredient necessary to deliver an effective dose asdescribed above.

The pharmaceutical compositions herein will contain, per unit dosageunit, e.g., tablet, capsule, powder, injection, suppository,teaspoonful, and the like, of from about 0.01 mg to about 1000 mg or anyamount or range therein, and may be given at a dosage of from about 0.01mg/kg to about 1.5 mg/kg, or any amount or range therein, preferablyfrom about 0.01 mg/kg/day to about 0.75 mg/kg, or any amount or rangetherein, preferably from about 0.05 mg/kg to about 0.5 mg/kg, or anyamount or range therein, preferably from about 0.1 mg/kg to about 0.5mg/kg, or any amount or range therein, of each active ingredient. Thedosages, however, may be varied depending upon the requirement of thepatients, the severity of the condition being treated and the compoundbeing employed. The use of either daily administration or post-periodicdosing may be employed.

Preferably these compositions are in unit dosage forms from such astablets, pills, capsules, powders, granules, sterile parenteralsolutions or suspensions, metered aerosol or liquid sprays, drops,ampoules, autoinjector devices or suppositories; for oral parenteral,intranasal, sublingual or rectal administration, or for administrationby inhalation or insufflation. Alternatively, the composition may bepresented in a form suitable for once-weekly or once-monthlyadministration; for example, an insoluble salt of the active compound,such as the decanoate salt, may be adapted to provide a depotpreparation for intramuscular injection. For preparing solidcompositions such as tablets, the principal active ingredient is mixedwith a pharmaceutical carrier, e.g. conventional tableting ingredientssuch as corn starch, lactose, sucrose, sorbitol, talc, stearic acid,magnesium stearate, dicalcium phosphate or gums, and otherpharmaceutical diluents, e.g. water, to form a solid preformulationcomposition containing a homogeneous mixture of a compound of thepresent invention, or a pharmaceutically acceptable salt thereof. Whenreferring to these preformulation compositions as homogeneous, it ismeant that the active ingredient is dispersed evenly throughout thecomposition so that the composition may be readily subdivided intoequally effective dosage forms such as tablets, pills and capsules. Thissolid preformulation composition is then subdivided into unit dosageforms of the type described above containing from about 0.01 mg to about1,000 mg, or any amount or range therein, of the active ingredient ofthe present invention. The tablets or pills of the novel composition canbe coated or otherwise compounded to provide a dosage form affording theadvantage of prolonged action. For example, the tablet or pill cancomprise an inner dosage and an outer dosage component, the latter beingin the form of an envelope over the former. The two components can beseparated by an enteric layer which serves to resist disintegration inthe stomach and permits the inner component to pass intact into theduodenum or to be delayed in release. A variety of material can be usedfor such enteric layers or coatings, such materials including a numberof polymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating treatment resistant depression described in thepresent invention may also be carried out using a pharmaceuticalcomposition comprising any of the compounds as defined herein and apharmaceutically acceptable carrier. The pharmaceutical composition maycontain between about 0.01 mg and about 1000 mg of the compound, or anyamount or range therein; preferably from about 0.05 mg to about 500 mgof the compound, or any amount or range therein, and may be constitutedinto any form suitable for the mode of administration selected. Carriersinclude necessary and inert pharmaceutical excipients, including, butnot limited to, binders, suspending agents, lubricants, flavorants,sweeteners, preservatives, dyes, and coatings. Compositions suitable fororal administration include solid forms, such as pills, tablets,caplets, capsules (each including immediate release, timed release andsustained release formulations), granules, and powders, and liquidforms, such as solutions, syrups, elixirs, emulsions, and suspensions.Forms useful for parenteral administration include sterile solutions,emulsions and suspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders; lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms in suitably flavored suspending or dispersing agentssuch as the synthetic and natural gums, for example, tragacanth, acacia,methyl-cellulose and the like. For parenteral administration, sterilesuspensions and solutions are desired. Isotonic preparations whichgenerally contain suitable preservatives are employed when intravenousadministration is desired.

To prepare a pharmaceutical composition of the present invention, aproduct prepared according to any of the process(es) as described hereinas the active ingredient is intimately admixed with a pharmaceuticalcarrier according to conventional pharmaceutical compounding techniques,which carrier may take a wide variety of forms depending of the form ofpreparation desired for administration (e.g. oral or parenteral).Suitable pharmaceutically acceptable carriers are well known in the art.Descriptions of some of these pharmaceutically acceptable carriers maybe found in The Handbook of Pharmaceutical Excipients, published by theAmerican Pharmaceutical Association and the Pharmaceutical Society ofGreat Britain.

Methods of formulating pharmaceutical compositions have been describedin numerous publications such as Pharmaceutical Dosage Forms: Tablets,Second Edition, Revised and Expanded, Volumes 1-3, edited by Liebermanet al; Pharmaceutical Dosage Forms: Parenteral Medications, Volumes 1-2,edited by Avis et al; and Pharmaceutical Dosage Forms: Disperse Systems,Volumes 1-2, edited by Lieberman et al; published by Marcel Dekker, Inc.

The following Examples are set forth to aid in the understanding of theinvention, and are not intended and should not be construed to limit inany way the invention set forth in the claims which follow thereafter.

In the Examples which follow, some synthesis products are listed ashaving been isolated as a residue. It will be understood by one ofordinary skill in the art that the term “residue” does not limit thephysical state in which the product was isolated and may include, forexample, a solid, an oil, a foam, a gum, a syrup, and the like.

Example 1: Preparation of (S)-Ketamine (+)-CSA Monohydrate Salt

rac-Ketamine free base (10 g, 42 mmol) and (+)-CSA (10 g, 42 mmol, 98mass %, 1 eq.) in methyl ethyl ketone (33.3 g) and water (1.85 g) werestirred at room temperature. The reaction mixture was then heated 50° C.and stirred for 1 h at this temperature. The resulting slurry was cooledto room temperature over 1 h. The resulting suspension stirred overnightand filtered. The wet cake was washed twice with methyl ethyl ketone (5g) to yield the title compound as a white solid (10.15 g of wetproduct). The material was dried for 6 h at 50° C., 10 mbar to yield(S)-Ketamine CSA salt as a white solid. Yield: 10.04 g. Purity: HPLC:100%. Enantiomeric purity: 96.4%. Assay corrected yield: 49%.

Example 2: Recrystallization of (S)-Ketamine (+)-CSA Monohydrate Salt

To (S)-ketamine-(+)-CSA monohydrate salt (10.1 g, 41.3 mmol) were addedmethyl ethyl ketone (33.3 g) and water (1.85 g). The reaction mixturewas then warmed to 80° C. A clear solution was observed to form. Thereaction mixture was then cooled to 50° C. (a slurry was observed toform). At this temperature, additional methyl ethyl ketone (33.3 g) wasadded. The resulting suspension was cooled to 20° C. over 1 h. Theresulting suspension was stirred overnight and filtered. The wet cakewas washed twice with methyl ethyl ketone (5 g) to yield the titlecompound as a white solid (8.84 g of wet product). The material wasdried for 1 h at 50° C., 10 mbar to yield (S)-Ketamine CSA salt as awhite solid. Yield: 8.81 g. Purity: HPLC: 100%. Enantiomeric purity:100%. Assay corrected yield: 86%.

Example 3: Preparation of (S)-Ketamine (+)-CSA Monohydrate Salt

rac-Ketamine free base (10 g, 42 mmol) and (+)-CSA (9.8 g, 42 mmol, 1eq.) in 2-methyl-THF (70 g) were stirred at room temperature. Water (6.3g) was added to yield a slurry. The slurry was heated to reflux (T=73°C.), resulting in the formation of a clear solution. The solution wasstirred at reflux temperature for 1 h, then cooled to 63° C. and seededwith small amounts (one spatula tip) of (S)-Ketamine-CSA salt.Crystallization was observed to start. The suspension was maintained atthis temperature for 1 h, cooled in 1 h to 50° C. and then to 20° C.,over an additional one hour. The resulting suspension was stirredovernight and filtered. The wet cake was washed twice with 2-methyl-THF(10 g) to yield the title compound as a white solid (9.1 g of wetproduct). The material is dried overnight at 50° C., 20 mbar to yield(S)-Ketamine CSA salt as a white solid. Yield: 9.06 g. Purity: HPLC:100%. Enantiomeric purity: 99.3%. Assay corrected yield: 45%.

Example 4: Preparation of (S)-Ketamine (+)-CSA Monohydrate Salt

rac-Ketamine free base (600 g, 2.524 mol) (+)-CSA (588 g, 2.531 mol, 1eq) in 2-Me-THF (4200 g) were stirred at room temperature. Then water(378 g) was added (formation of a slurry was observed). The slurry washeated to reflux (T=72-73° C.). A clear solution was observed to form.The solution was stirred at this temperature for about 10 minutes. Themixture was cooled to 63° C. within 20 min and seeded with(S)-Ketamine-(+)-CSA monohydrate salt (2 g). Crystallization wasobserved to start. The resulting suspension was maintained at thistemperature for 1 h. Then the following cooling profile was applied:cooling to 59° C. in 1 h, cooling to 52° C. in 1 h, cooling to 38° C. in1 h, cooling to 20° C. in 40 min, cooling to 0° C. in 20 min. Thesuspension was stirred for 6 h-16 h and filtered. The wet cake waswashed with 2-Me-THF (a total of 2150 g) containing 2% of water (2107 g2-Me-THF, 43 g water) in 3 portions and wet product were obtained aswhite solid (654 g). The material was dried overnight at 50° C. at 20mbar and (S)-Ketamine CSA salt monohydrate (573 g) was obtained as whitesolid. Enantiomeric purity: 99.21. Assay corrected yield: 47%. Watercontent: 3.84%.

Example 6: Recrystallization of (S)-Ketamine (+)-CSA Monohydrate Salt

(S)-Ketamine-(+)-CSA monohydrate (50.0 g, 102.46 mmol) was suspended inTHF (375 g) and water (25 g). The resulting mixture was heated to reflux(clear solution, T=64° C.). The clear solution was cooled to 50° C. andseeded with crystals of (S)-Ketamine-(+)-CSA monohydrate (0.25 g).Crystallization was observed to start and a suspension was formed, whichwas stirred for 1 h at this temperature. The suspension was cooled to 0°C. within 8 h and stirred for overnight at this temperature. The productwas filtered off and washed with THF (3×25 g). The wet product (45.8 g)was dried overnight at 50° C. at 20 mbar to yield (S)-Ketamine-(+)-CSAmonohydrate are isolated as white solid (45.4 g). Enantiomeric Purity:100.00. Assay Corrected Yield: 91%. Water Content: 3.84%.

Example 7: Preparation of (R)-Ketamine (−)-CSA Monohydrate Salt

rac-Ketamine free base (10 g, 42 mmol) and (−)-CSA (9.8 g, 42 mmol, 1eq.) in 2-methyl-THF (70 g) were stirred at room temperature. Water (6.3g) was added to yield a slurry. The slurry was heated to reflux (T=72°C.), resulting in the formation of a clear solution. The solution wasstirred at reflux temperature for 1 h, then cooled to 63° C. 0.5 ml of asuspension prepared from 100 mg (R)-ketamine, and 98 mg(−)-camphor-10-sulfonic acid dissolved in 1.5 g of THF and 8 μg of water(spontaneous crystallization) was added. The reaction mixture becameturbid. The formed suspension was cooled to 59° C. within 1 h, thenfurther cooled in 1 h to 52° C., in 1 h to 38° C., in 2 h to 20° C., andin 2 h to 0° C. The formed suspension was further stirred at 0° C.overnight. The resulting suspension was filtered, and the wet cake waswashed twice with a mixture of 2-methyl-THF (9.6 g) and water (0.4 g) toyield the title compound as a white solid (10.5 g of wet product). Thematerial was dried overnight at 50° C., 20 mbar to yield (R)-Ketamine(−)-CSA salt as a white solid. Yield: 9.3 g. Assay corrected yield: 43%.Purity: HPLC: 100%. Enantiomeric purity: 99.38%, purity 100%, assay95.23%.

Example 8: Preparation of (S)-Ketamine Hydrochloride Salt from theMother Liquor of Example 7

To the mother liquor of Example 7 (which contains (S)-ketamine and(−)-camphor-10-sulfonic acid dissolved in a methyl-THF/water mixture(10.9:1)) was added HCl gas (0.9 g) at ambient temperatures over 2 min.Spontaneous crystallization of a solid was observed (pH of the solution0-1). After stirring for 30 min the solids were filtered off, and thewet cake was rinsed twice with methyl-THF (5.0 g each time). Theresulting solids (5.8 g wet) were dried in vacuum at 50PC. The motherliquor (107.45 g) contains 82% (S)-ketamine and 18% (R)-ketamine. Yield3.91 g; Assay Corrected Yield (with respect to the used rac-ketamine inexperiment 7: 34% (68% with respect to (S)-ketamine). EnantiomericPurity: 99.78%. Water Content: 0.23%, purity 99.98%, assay 97.56%

Example 9: Classical Resolution Screening Experiments

Unless otherwise noted, all resolution experiments were performed on a 1mmol scale of (±)-ketamine free base and with addition of 0.5mol-equivalent of the selected acidic resolving agent in 3.5 mL ofsolvent. The acidic resolving agents tested were as follows:

ID No. Structure/Name 1

(1S)-(+)-10- camphorsulphonic acid 2

(S)-(−)-phencyphos (P1(+)) 3

L(+)-tartaric acid 4

L(−)-O,O′-DBTA 5

L(−)-O,O′-DTTA

D(+)-O,O′-DATA 7

L(−)-2-pyrrolidone-5- carboxylic acid 8

N-Bz-L-Asp-OH 9

N-Bz-L-Glu-OH 10

(S)-(+)-mandelic acid 11

(S)-(+)-2-(4-chlorophenyl)-3- methylbutanoic acid 12

(S)-(+)-naproxen 13

(S)-N-tosyl-valine 14

(R)-N-Tosyl-phenylglycine 15

(R)-N-Benzoyl-phenylglycine 16

(R)-(−)-1,1′-bisnaphthyl-2,2′-diyl- hydrogenphosphate

Preparation of (±)-Ketamine Free Base

Racemic ketamine.HCl (15.0 g, 54.7 mmol) was dissolved in 100 mL ofwater under stirring. To the solution was added 100 mL CHCl₃ and undervigorous stirring basified by drop-wise addition of a solution of 2.40 gNaOH (60 mmol) in 30 mL of water. The white precipitate that was formedwas directly extracted into the CHCl₃ layer (clear solution). Themixture was transferred into a separation funnel and separated. Theaqueous phase was extracted again with 100 mL chloroform and then with50 mL of chloroform. The combined chloroform layers were washed with 50mL of water, dried over Na₂SO₄ and concentrated on a Rotavap to yield awhite crystalline solid (solidified oil). Yield: 12.88 g of white solid(54.2 mmol, 99%); NMR confirmed ketamine free base.

The procedure was repeated with 10.15 g (36.9 mmol) of racemic ketamineand yielded 8.73 g (36.7 mmol, 99.5%) of free ketamine as a white solid.

RS1: Resolution Screening Experiments in Methanol:

Ketamine free base (3.93 g, 16.5 mmol) was dissolved in 15 mL methanol(slightly warmed for dissolution), transferred to a 25 mL volumetricflask and the flask filled to 25 mL with methanol (1 mmol=1.52 mL). Theweight of this solution was 21.0 g (1 mmol=1.27 g). The resolving agentwas dissolved/suspended in 1.60 g (2.0 mL) of methanol.

At room temperature 1.27 g (1.0 mmol) of the prepared ketamine free basesolution in methanol was added to the prepared resolving agent inmethanol mixture. All resulting solutions were observed to become clear,except Exp. #1.2 and #1.9, which were heated to effect dissolution.After standing for 22 h at room temperature, all solutions were stillclear. The screw caps were removed after 2 days, to allow slowevaporation. After 5 days, most of the solvent was evaporated and inmost vials a thick oil remained, as indicated in Table RS1, below. Tothe vials with a solid layer was added 1 mL of MeOH to re-dissolve anysolids. Addition of the methanol resulting in most of the solidre-dissolving, and then 3 mL of cyclo-pentyl methyl ether (CPME) asanti-solvent was added. After 4 hours standing, all vials were againopened again for slow evaporation. After 2 days slow evaporation of theCPME to ˜2 mL, a thick turbid oil was observed to form in some of thevials (see Table RS1). These vials were closed and heated to reflux fordissolution (if necessary a few drops of MeOH were added fordissolution). In vials of Exp. #1.4, #1.5 and #1.9 oils were formedagain. In vial of Exp. #1.16 a solid was formed and the mother liquid(and 0.5 mL CPME washing) was removed with a pipette, although the solidexhibited an e.e. <5%. Vials/experiments which did not yield a solidafter 7 days (with addition of CPME as anti-solvent) were held at roomtemperature for up to an additional 7 days (total of 14 days) in aneffort to effect crystallization.

Table 6 below summarized the conditions and results of screeningexperiments with the 16 resolving agents identified above, usingmethanol as the solvent. Note: in experiments where no observation isnoted in the columns “5-day evaporation” and/or “7 days+CPME, up to 14days”, no solid or oil was obtained.

TABLE 6 Resolution Screening Results, MeOH solvent mg* 5 day 7 days +Exp Resolving (0.5 evapo- CPME, up to # Agent mmol) ration 14 days 1.1(1S)-(+)-10- 116 camphorsulfonic acid 1.2 (S)-(+)- 121 solid phencyphos(P1(+)) 1.3 L(+)-tartaric acid  75 8 days: turbid (oil layer) 14 d:solidified 1.4 L(−)-O,O′-DBTA 188 9 days: turbid oil 1.5 L(−)-O,O′-DTTA  193 9 9 days: turbid oil 1.6 D(+)-O,O′-DATA 209 9 days: turbid oil(clear after heating + MeOH) 1.7 L(−)-2-  65 5 d: solid 8 days:pyrrolidone-5- (needles) + turbid oil carboxylic MeOH: re- (clear afteracid dissolved heating + MeOH) 1.8 N-Bz-L-Asp-OH 119 9 days: turbid oil1.9 N-Bz-L-Glu-OH 126 solid turbid oil after addition CPME 1.10 (S)-(+)-76 mandelic acid 1.11 (S)-(+)-2-(4- 106 solid 14 days: solidchlorophenyl)-3- in oil after methylbutanoic evaporation acid 1.12(S)-(+)-Naproxen 115 solid + MeOH: re- dissolved 1.13 (S)-N-Tosyl-valine136 solid 1.14 (R)-N-Tosyl- 153 solid phenylglycine 1.15 (R)-N- 128solid Benzo- ylphen- ylglycine 1.16 (R)-(−)-1,1′-   87** 9 days: turbidoil, bisnaphthyl-2,2′-diyl crystallized hydrogenphosphate after heatingSolid: 78 mg e.e. <5% ML: e.e. <5% *+/−1 mg; **0.25 mmol resolving agentin 1 mL methanol, added 0.64 g (0.50 mmol) ketamine MeOH solution

In summary: no crystals were obtained when methanol was used as thesolvent. After evaporation of methanol, the obtained oils werere-dissolved in a small amount of methanol and CPME (as anti-solvent).In three experiments, #1.3, #1.11 and #1.16 some solids were obtained.For Exp. #1.1, the % ee of the mother liquor and solid were determinedto be very low (<5%).

RS2: Resolution Screening Experiments in 2-Butanone (MEK)

Ketamine free base (3.93 g, 16.5 mmol) was dissolved in 15 mL 2-butanone(slightly warmed for dissolution), transferred to a 25 mL volumetricflask and the flask filled to 25 mL with 2-butanone (1 mmol=1.52 mL).The weight of this solution was 21.29 g (1 mmol=1.29 g). The resolvingagent was dissolved/suspended in 1.60 g (2.0 mL) of 2-butanone.

At room temperature 1.29-1.32 g (1.0 mmol) of the prepared ketaminesolution in 2-butanone was added to the prepared resolving agentsolution. All solution became clear, except vials in Exp. #2.3, #2.6,#2.7, #2.8, #2.9, #2.14 and #2.15. These vial were heated fordissolution. In vials of Exp. #2.3 and #2.9 some solid remained, whereasvials for Exp. #2.14 and #2.15 became opaque. After 20 h at roomtemperature, the vials of Exp. #2.3 (tartaric acid), #2.7 (pyroGlu) and#2.9 (N-BzGlu) contained some crystals. The solution in vials of Exp.#2.14 and #2.15 became slightly turbid. In all other vials the solutionremained clear, therefore after 2 days, the screw caps of these vialswere removed for slow evaporation. After 5 days slow evaporation to halfvolume no additional crystallization was observed to occur. After 7 daysthe clear solutions in vials of Exp #2.4 and #2.5 were seeded with theL-(−)-DATA salt of S-ketamine (prepared as described in RS5: #4.2 whichfollows), however, no crystallization occurred and the seed crystalsdissolved. Vials/experiments which did not yield a solid after 7 dayswere held at room temperature for up to an additional 7 days (total of14 days) in an effort to effect crystallization.

Table 7 below summarized the results of screening experiments with 16resolving agents and 2-butanol as the solvent. NOTE: Where noobservation is noted in the columns “20 h room temperature”, “5-day slowevapor.” and/or “7-14 days”, no solid or oil was obtained.

TABLE 7 Resolution Screening Results, 2-Butanone (MEK) mg 5 day,Resolving (0.5 20 h slow 7-14 Exp # agent eq.) RT evapor. days 2.1(1S)-(+)-10- 116 camphorsulfonic acid 2.2 (S)-(+)- 121 phencyphos(P1(+)) 2.3 L(+)-tartaric  75 crystals 8 days: acid Solid: 183 mg e.e.58% (S) ML: e.e. 31% (R) 2.4 L(−)-O,O′-DBTA 188 2.5 L(−)-O,O′-DTTA 1932.6 D(+)-O,O′-DATA 209 crystals 8 days: @ 24 h Solid: 245 mg e.e. 61%(S) ML: e.e. 32% (R) 2.7 L(−)-2-  65 few thick oil pyrrolidone-5-crystals carboxylic acid 2.8 N-Bz-L-Asp-OH 119 8 d: few crystals 2.9N-Bz-L-Glu-OH 126 crystals 8 days: Solid: 149 mg e.e. <5% ML: e.e. <5%2.10 (S)-(+)-mandelic  76 acid 2.11 (S)-(+)-2-(4- 106 8 d: fewchlorophenyl)-3- crystals methylbutanoic acid 2.12 (S)-(+)- 115 Naproxen2.13 (S)-N-Tosyl- 136 valine 2.14 (R)-N-Tosyl- 153 turbid 8 days:phenylglycine turbid 2.15 (R)-N- 128 turbid pink Benzoylphenyl- solutionglycine 2.16 (R)-(−)-1,1′-   87** bisnaphthyl-2,2′- diyl hydrogenphosphate *+/−1 mg; **0.25 mmol resolving agent in 1 mL 2-butanone,added 0.66 g (0.50 mmol) ketamine solution

As shown in Table RS2 above, when 2-butanol was used as the solvent,L-(+)-tartaric acid and D-(+)-O,O′-DATA yielded a solid, with someresolution of the (S)- and (R)-ketamine stereoisomers. AlthoughD-(+)-O,O′-DATA yielded a solid, the solid was determined (by ¹H NMR) tobe a 1:1 salt of the undesired enantiomer, containing 1 mol of2-butanone as a solvate molecule. Additionally, N-Bz-L-Glu-OH yielded asolid, although analysis of this solid indicated that no significantamount of resolution was achieved.

RS3: Resolution Screening Experiments in 10:1 v:v IPA/H₂O

Ketamine free base (3.93 g, 16.5 mmol) was dissolved in a 10:1 v:vmixture of 2-propanol/water to a total volume of 25 mL (warmed fordissolution and kept hand warm to prevent crystallization). The weightof this solution was 21.1 g (1 mmol=1.27 g=1.52 mL). The resolving agentwas dissolved/suspended in 1.60 g (2.0 mL) of a 10:1 v:v mixture of2-propanol/water.

At room temperature 1.27-1.30 g (1.0 mmol) of the prepared ketaminesolution was added to the prepared resolving agent solution, except Exp#3.12 where 1.43 g (1.12 mmol) of the prepared ketamine solution wasadded to the corresponding prepared resolving agent solution. Theresulting solutions became clear, except Exp #3.2, #3.3, #3.5, #3.6,#3.9, #3.14 and #3.15 which were heated for dissolution. In the vial ofExp. #3.9 some solid remained even after heating. After 18 h at roomtemperature only the vial of Exp. #3.9 contained some crystals (possiblythe resolving agent) and the vial of Exp. #3.15 became slightly turbid.In all other vials the solution remained clear, therefore the screw capswere removed for slow evaporation to half volume over 5 days. In 4 vialsa crystal ring was formed on the glass wall above the surface (possibleMarangoni-like effect) that was scratched back into the mother liquid.For Exp #3.8 these crystals were observed to re-dissolve.Vials/experiments which did not yield a solid were held at roomtemperature for up to a total of 14 days, in an effort to effectcrystallization.

Table 8 below summarized the results of screening experiments with 16resolving agents and the 10:1 v:v mixture of IPA:water as the solvent.Note: Where no observation is noted in the columns “18 h RT”, “5 day,slow evap.” and/or “6-14 day”, no solid or oil was obtained.

TABLE 8 Resolution Screening Results, 10:1 v:v IPA/H₂O mg 5 day ExpResolving (0.5 18 h slow 6-14 # agent eq) RT evap. days 3.1 (1S)-(+)-10-116 camphor- sulfonic acid 3.2 (S)-(+)- 121 phencyphos (P1(+)) 3.3 L(+)- 75 tartaric acid 3.4 L(−)-O,O′-DBTA 188 3.5 L(−)-O,O′-DTTA 193 3.6D(+)-O,O′-DATA 209 3.7 L(−)-2-  65 crystal 8 days: pyrrolidone- ringSolid: 71 mg 5-carboxylic e.e. <5% acid ML: e.e. <5% 3.8 N-Bz-L-Asp-OH119 crystal ring, re- dissolved in ML 3.9 N-Bz-L-Glu-OH 126 few crystal8 days: crystals ring Solid: 92 mg e.e. <5% ML: e.e. <5% 3.10 (S)-(+)- 76 mandelic acid 3.11 (S)-(+)-2-(4- 106 6 d: slow 8 days:chlorophenyl)-3- crystal- Solid: 83 mg methylbutanoic lization e.e. <5%acid (needles) ML: e.e. <5% 3.12 (S)-(+)- 115 6 d: 8 days: Naproxen slowSolid: crystal- 103 mg lization e.e. <5% (needles) ML: e.e. <5% 3.13(S)-N-Tosyl- 136 valine 3.14 (R)-N-Tosyl- 153 Turbid phenylglycine 3.15(R)-N-Benzoyl- 128 turbid crystal 8 days: phenylglycine ring Solid: 39mg e.e. <5% ML: e.e. <5% 3.16 (R)-(−)-1,1′-   87** bisnaphthyl-2,2′-diyl hydrogen phosphate *+/−1 mg; **0.25 mmol resolving agent in 1 mL2-PrOH/H2O 10:1, added 0.65 g (0.50 mmol) ketamine solution

As shown in Table 8 above, when a 10:1 v:v IPA/water mixture was used asthe solvent, L(−)-2-pyrrolidone-5-carboxylic acid, N-Bz-L-Glu-OH,(S)-(+)-2-(4-chlorophenyl)-3-methylbutanoic acid, (S)-(+)-Naproxen and(R)—N-Benzoyl-phenylglycine yielded a solid, although analysis of saidsolids indicated that no significant amount of resolution was achievedfor any of these resolving agents.

RS4: Preparation of L-(−)-DATA Salt of S-Ketamine

Ketamine (racemic, 238 g, 1 mmol) was dissolved in MEK (3.5 mL) and theresulting solution was added to dry L-(−)-DATA (0.5 mmol). The mixture(in a vial) was warmed to reflux to complete dissolution and thencooled. Slow crystallization started after 24 hours (scratching withspatula), to yield a solid (167 mg, 23%) which exhibited 54% e.e.

The resolution screening experiments described above confirmed thatL-tartaric acid is useful as a resolving agent for ketamine, andsuggested that D-(+)-DATA, and L-(−)-DATA (derivatives of tartaricacid), may also be effective.

Although additional optimization experiments with D-(+)-DATA andL-(−)-DATA were completed, for large scale manufacturing, material costsfor these resolving agents are not cost-effective and/or prohibitive.

Example 10: Resolution Experiments: (+)-CSA in Organic Solvent/WaterMixture

Although contrary to the results of the screening experiments describedabove and contrary to the teachings in HUDYMA, T. W., et al. (DE 2062620A), which disclosed that attempts at resolution of ketamine withcamphorsulfonic acid (CSA) were unsuccessful, additional experimentswere nonetheless undertaken in an effort to develop a method for theresolution of ketamine using camphorsulfonic acid in aqueous solventmixture.

Table 9 below details three representative experiments reacting racemicketamine with (+)-CSA in (a) a mixture of THF and water, (b) a mixtureof acetone and water, and (c) a mixture of 2-methyl-THF and water. Eachexperiment resulted in formation of (S)-ketamine•(+)-CSA salt in highenantiomeric excess, as noted in the Table below. All reaction mixtureswere heated, with stirring as noted. The resulting precipitate was thenisolated by filtration, washed with the corresponding organic solvent(no water) and dried at under vacuum 50° C.

TABLE 9 Preparation of (+)-CSA salt of S-Ketamine E-1 E-2 E-3 (Rac)- 10g 5 g 10 g Ketamine (+)-CSA 5.3 g 2.65 g 9.8 g Solvent 60 g THF + 40 gAcetone + 60 g 2-Me-THF + 1.2 g H₂O 2.5 g H₂O 3.8 g H₂O Rxn 63° C. for30 min; 55° C.; 73° C.; mixture not Conditions 50° C., 1 hr; 10° C., 2hr cooling; dissolved; 20° C., 2 hr; 10° C., 30 min, stirring; add 10 g2-Me-THF + stirred overnight; continued stirring 1.9 g H₂O; overnight;63° C., seeded & stirred for 1 hr; 50° C. 1 hr, 20° C. 1 hr, 2 hrstirring Notes: first crystallization crystallization observed Seeded at63° C. observed during at 42° C. heating to 63° C. Yield^(a) 8.12 g(39.4%) 3.53 g (34.3%) 9.24 g (44.6%) % ee 97.3% ee 98.0% ee 98.4% ee^(a)Maximum yield of desired product (S-enantiomer) from racemate is50%.

Formulation Example 1 Solid, Oral Dosage Form—Prophetic Example

As a specific embodiment of an oral composition, 100 mg of a productprepared as in Example 1, 2 or 3 is formulated with sufficient finelydivided lactose to provide a total amount of 580 to 590 mg to fill asize 0 hard gel capsule.

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variations, adaptations and/or modifications as come withinthe scope of the following claims and their equivalents.

What is claimed is:
 1. An (S)-camphorsulfonic acid salt of S-ketamine.2. An (S)-camphorsulfonic acid salt of S-ketamine as in claim 1, whereinthe salt is a monohydrate.
 3. A crystalline monohydrate form of(S)-camphorsulfonic acid salt of S-ketamine.
 4. A crystallinemonohydrate form as in claim 3 comprising the following pXRD peaks:position [°2θ] d-spacing [Å] relative intensity [%] 7.76 11.38 58.038.11 10.89 21.58 12.75 6.94 24.89 13.13 6.74 55.99 13.31 6.65 23.9613.64 6.49 31.52 14.92 5.93 100.00 15.51 5.71 32.12 15.71 5.64 28.4618.45 4.80 43.84 24.22 3.67 25.66 25.26 3.52 28.46 27.33 3.26 51.32.


5. A crystalline monohydrate form as in claim 3 comprising the followingpXRD peaks: position [°2θ] d-spacing [Å] relative intensity [%] 7.7611.38 58.03 8.11 10.89 21.58 12.75 6.94 24.89 13.13 6.74 55.99 13.316.65 23.96 13.64 6.49 31.52 14.92 5.93 100.00 15.51 5.71 32.12 15.715.64 28.46 18.45 4.80 43.84 21.29 4.17 12.49 22.38 3.97 14.87 23.26 3.8210.45 24.22 3.67 25.66 25.26 3.52 28.46 26.76 3.33 13.93 27.33 3.2651.32 28.21 3.16 12.32 29.13 3.06 11.05.


6. A process for the preparation of a monohydrate form of(S)-camphorsulfonic acid salt of S-ketamine comprising

reacting ketamine with (S)-camphorsulfonic acid, wherein the(S)-camphorsulfonic acid is present in an amount in the range of fromabout 0.5 to about 2.0 molar equivalents (relative to the molar amountof ketamine); in the presence of water, wherein the water is present inan amount in the range of from about 3.5% to about 15%; in an organicsolvent; at a temperature in the range of from about 20° C. to aboutsolvent reflux temperature; to yield the corresponding monohydrate formof (S)-camphorsulfonic acid salt of S-ketamine; wherein the monohydrateform of (S)-camphorsulfonic acid salt of S-ketamine is present in anenantiomeric excess in the range of from about 50% to about 100%.
 7. Aprocess as in claim 6, wherein the (S)-camphorsulfonic acid is presentin an amount in the range of from about 0.75 to about 1.2 molarequivalents.
 8. A process as in claim 6, wherein the (S)-camphorsulfonicacid is present in an amount in the range of from about 0.9 to about 1.1molar equivalents.
 9. A process as in claim 6, wherein the water ispresent in an amount in the range of from about 5% to about 10%.
 10. Aprocess as in claim 6, wherein the water is present in an amount in therange of from about 6% to about 8%.
 11. A process as in claim 6, whereinthe organic solvent is selected from the group consisting of methylethyl ketone and 2-methyl-THF.
 12. A process as in claim 6, wherein theorganic solvent is 2-methyl-THF.
 13. A process as in claim 6, whereinthe ketamine is reacted with (S)-camphorsulfonic acid at a temperaturein the range of from about 30° C. to about 100° C.
 14. A process as inclaim 6, wherein the ketamine is reacted with (S)-camphorsulfonic acidat a temperature of about 50° C. to about 80° C.
 15. A process as inclaim 6, wherein the monohydrate form of (S)-camphorsulfonic acid saltof S-ketamine is present in an enantiomeric excess in the range of fromabout 75% to about 100%.
 16. A process as in claim 6, wherein themonohydrate form of (S)-camphorsulfonic acid salt of S-ketamine ispresent in an enantiomeric excess in the range of from about 90% toabout 100%.
 17. A process as in claim 6, wherein the monohydrate form of(S)-camphorsulfonic acid salt of S-ketamine is present in anenantiomeric excess of greater than or equal to about 96%.
 18. A processfor the preparation of a monohydrate form of (S)-camphorsulfonic acidsalt of S-ketamine comprising

reacting racemic ketamine with (S)-camphorsulfonic acid, wherein the(S)-camphorsulfonic acid is present in an amount of about 1 molarequivalents (relative to the molar amount of ketamine); in the presenceof water, wherein the water is present in an amount of in the range offrom about 6% to about 8%; in 2-methyl-THF; at a temperature of about70° C.; to yield the corresponding monohydrate form of(S)-camphorsulfonic acid salt of S-ketamine; wherein the monohydrateform of (S)-camphorsulfonic acid salt of S-ketamine is present in anenantiomeric excess in the range of from about 80% to about 100%.
 19. Aproduct prepared according to the process of any of claim
 6. 20. Aprocess according to claim 6, further comprising (a) reacting themonohydrate form of (S)-camphorsulfonic acid salt of S-ketamine with abase; in a solvent or mixture of solvents; to yield S-ketamine as a freebase; and (b) reacting the S-ketamine free base with HCl; to yield thecorresponding S-ketamine hydrochloride salt.
 21. An (R)-camphorsulfonicacid salt of R-ketamine.
 22. An (R)-camphorsulfonic acid salt ofR-ketamine as in claim 21, wherein the salt is crystalline.
 23. An(R)-camphorsulfonic acid salt of R-ketamine as in claim 21, wherein thesalt is a hydrate.
 24. An (R)-camphorsulfonic acid salt of R-ketamine asin claim 21, wherein the salt is a monohydrate.
 25. A process for thepreparation of (R)-camphorsulfonic acid salt of R-ketamine comprising

reacting ketamine with (R)-camphorsulfonic acid, wherein the(R)-camphorsulfonic acid is present in an amount in the range of fromabout 0.5 to about 2.0 molar equivalents (relative to the molar amountof ketamine); in the presence of water, wherein the water is present inan amount in the range of from about 3.5% to about 15%; in an organicsolvent; at a temperature in the range of from about 20° C. to aboutsolvent reflux temperature; to yield a product mixture comprising(R)-camphorsulfonic acid salt of S-ketamine as a solid and S-ketamine;wherein the (R)-camphorsulfonic acid salt of R-ketamine is present in anenantiomeric excess in the range of from about 50% to about 100%.
 26. Aprocess as in claim 25, further comprising (a) filtering the productmixture to yield the (R)-camphorsulfonic acid salt of R-ketamine as asolid and a filtrate comprising S-ketamine; (b) reacting the S-ketaminewith HCl; to yield the corresponding S-ketamine hydrochloride salt. 27.A process for the preparation of S-ketamine hydrochloride comprising thefollowing steps: Step 1:

reacting ketamine with (R)-camphorsulfonic acid, wherein the(R)-camphorsulfonic acid is present in an amount in the range of fromabout 0.5 to about 2.0 molar equivalents (relative to the molar amountof ketamine); in the presence of water, wherein the water is present inan amount in the range of from about 3.5% to about 15%; in an organicsolvent; at a temperature in the range of from about 20° C. to aboutsolvent reflux temperature; to yield a product mixture comprising(R)-camphorsulfonic acid salt of S-ketamine as a solid and S-ketamine insolution; wherein the (R)-camphorsulfonic acid salt of R-ketamine ispresent in an enantiomeric excess in the range of from about 50% toabout 100%; Step 2:

filtering the product mixture to yield the (R)-camphorsulfonic acid saltof R-ketamine as a solid and a filtrate comprising S-ketamine; and Step3:

reacting the S-ketamine with HCl; to yield the corresponding S-ketaminehydrochloride salt.
 28. A product prepared according to the process ofclaim
 25. 29. A product prepared according to the process of claim 27.30. A process for the preparation of S-ketamine or S-ketaminehydrochloride as described herein.
 31. A product prepared according toany of the processes described herein.